NEW YORK -- An experimental Alzheimer's disease vaccine aimed at tangles of tau protein in the brain slowed deterioration of function in mice, reported investigators here.
NEW YORK, Aug. 21 -- An experimental vaccine aimed at tangles of tau protein, the lesser-known Alzheimer's pathology, slowed deterioration of function and frontotemporal dementia in mice, found investigators here.
When injected into mice bred to develop abnormal tangles of tau protein -- a pathologic hallmark of Alzheimer's dementia along with beta-amyloid plaque -- the vaccine induced antibodies to tau that crossed the blood-brain barrier and reduced the tau burden, reported Einar Sigurdsson, Ph.D., of New York University.
Immunized mice also had better behavioral and motor function at five and eight months of age than controls, the authors reported in the Aug. 22 issue of the Journal of Neuroscience.
"This approach may have extensive therapeutic implications because you can specifically target the problematic protein," said Dr. Sigurdsson. "Tau aggregates are inside the cell, making it especially difficult to develop a therapy to target and clear them from the cell."
Tau is a soluble protein involved in normal cellular function. In Alzheimer's disease and other forms of dementia, however, abnormally phosphorylated tau has been identified at the primary component of pathologic neurofibrillary tangles in neurons of the cerebral cortex and temporal lobe structures such as the hippocampus and amygdala.
"Although tau pathology is likely to occur after beta-amyloid aggregation based on Down's syndrome studies, analyses of Alzheimer's disease brains and mouse models indicate that these pathologies are likely to be synergistic," the authors wrote. "Hence, targeting both pathologies may substantially increase treatment efficacy."
Vaccines aimed at preventing or reversing pathology of Alzheimer's disease by inducing immunity against beta-amyloid protein showed promise in animals studies, but the first human trials were abandoned in 2002, after 12 of 360 patients developed severe inflammation of the central nervous system.
"There has been so much focus on beta-amyloid related therapy, but there has been relatively little done in the tau field, and one of the main problems with the tau field has been the access to the pathological tau protein," Dr. Sigurdsson said in an interview.
In the current study, Dr. Sigudsson and colleagues immunized transgenic P301L tangle-model mice with a phosphorylated tau epitope, which induced the development of anti-tau antibodies that were shown in laboratory studies to recognize pathological tau protein in the brain.
When the mice were subjected to behavioral tests that require extensive motor coordination, the authors found that at five months of age the immunized animals were able to stay longer on an accelerating rotarod (P<0.002) had fewer foot slips while negotiating a traverse beam (P<0.001), and had faster locomotor function (P=0.004) than unvaccinated tangle model mice.
The differences between the treated and untreated mice in the performance of the rotarod and traverse beam task persisted at eight months, although the between-group difference was smaller than at five months. There were no significant differences in locomotor activity at eight months, however.
The authors also observed a correlation between tau pathology in the motor cortex and performance on motor-intensive tasks.
Their findings suggest that it may be possible to directly treat tau pathology to slow or possibly prevent neuronal damage from Alzheimer's disease or frontotemporal dementias, Dr. Sigurdsson said.
"This is something very new showing that immunotherapy actually enables you to get these antibodies into the brain and into the neurons," he said, "and I think that the reason for that is that these animals probably have an impaired blood-brain barrier and altered uptake of proteins, including antibodies, into the neurons that is related to the pathology."
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